Wei Han and Klaus Schulten.
Characterization of folding mechanisms of Trp-cage and WW-domain
by network analysis of simulations with a hybrid-resolution model.
Journal of Physical Chemistry B, 117:13367-13377, 2013.
(PMC: 3811923)
HAN2013
In this study, we apply a hybrid-resolution model, namely, PACE, to characterize the free
energy surfaces (FESs) of Trp-cage and a WW-domain variant along with the respective
folding mechanisms. Unbiased, independent simulations with PACE are found to achieve
together multiple folding and unfolding events for both proteins, allowing us to perform
network analysis of the FESs to identify folding pathways. PACE reproduces for both
proteins expected complexity hidden in the folding FESs, in particular metastable non-
native intermediates. Pathway analysis shows that some of these intermediates are,
actually, on-pathway folding intermediates and that intermediates kinetically closest to the
native states can be either critical on-pathway or off-pathway intermediates, depending on
the protein. Apart from general insights into folding, specific folding mechanisms of the
proteins are resolved. We find that Trp-cage folds via a dominant pathway in which
hydrophobic collapse occurs before the N-terminal helix forms; full incorporation of Trp6
into the hydrophobic core takes place as the last step of folding, which, however, may not
be the rate-limiting step. For the WW-domain variant studied, we observe two main folding
pathways with opposite orders of formation of the two hairpins involved in the structure;
for either pathway, formation of hairpin 1 is more likely to be the rate-limiting step.
Altogether, our results suggest that PACE combined with network analysis is a
computationally efficient and valuable tool for the study of protein folding.
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